Naltrexone is marketed as its hydrochloride salt, naltrexone hydrochloride, under the trade names Revia and Depade. A once-monthly extended-release injectable formulation is marketed under the trade name Vivitrol. VIVITROL is indicated for the treatment of alcohol dependence in patients who are able to abstain from alcohol in an outpatient setting prior to initiation of treatment with VIVITROL. VIVITROL is indicated for the prevention of relapse to opioid dependence, following opioid detoxification. Naltrexone is a pure opiate antagonist and has little or no agonist activity. The mechanism of action of naltrexone in alcoholism is not understood; however, involvement of the endogenous opioid system is suggested by preclinical data. Naltrexone is thought to act as a competitive antagonist at mc, κ, and δ receptors in the CNS, with the highest affinity for the μ receptor. Naltrexone competitively binds to such receptors and may block the effects of endogenous opioids. This leads to the antagonization of most of the subjective and objective effects of opiates, including respiratory depression, miosis, euphoria, and drug craving. The major metabolite of naltrexone, 6-β-naltrexol, is also an opiate antagonist and may contribute to the antagonistic activity of the drug. Low dose naltrexone is an “off label” use of naltrexone. Normal naltrexone usage to break addictions is 50mg – 100mg. Usage of low dose naltrexone ranges in the area of 3 mg – 4.5 mg dosing and is prescribed in an oral pill form and is quite inexpensive. For people with multiple sclerosis, the dosage of LDN ranges from 1.5 to 4.5 ml per day.

Buprenorphine is an opioid analgesic, used to treat opioid addiction, moderate acute pain, and moderate chronic pain. Buprenorphine is a partial agonist at the mµ-opioid receptor and an antagonist at the kappa-opioid receptor. One unusual property of buprenorphine observed in vitro studies is its very slow rate of dissociation from its receptor. This could account for its longer duration of action than morphine, the unpredictability of its reversal by opioid antagonists, and its low level of manifest physical dependence. The principal action of the therapeutic value of buprenorphine is analgesia and is thought to be due to buprenorphine binding with high affinity to opioid receptors on neurons in the brain and spinal cord. Buprenorphine produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation. Buprenorphine causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Buprenorphine produces peripheral vasodilation, which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension.

Naloxone, sold under the brand name Narcan among others, is a medication used to block the effects of opioids, especially in overdose. Naloxone has an extremely high affinity for μ-opioid receptors in the central nervous system (CNS). Naloxone is a μ-opioid receptor (MOR) inverse agonist, and its rapid blockade of those receptors often produces rapid onset of withdrawal symptoms. Naloxone also has an antagonist action, though with a lower affinity, at κ- (KOR) and δ-opioid receptors (DOR). If administered in the absence of concomitant opioid use, no functional pharmacological activity occurs (except the inability for the body to combat pain naturally). In contrast to direct opiate agonists, which elicit opiate withdrawal symptoms when discontinued in opiate-tolerant people, no evidence indicates the development of tolerance or dependence on naloxone. The mechanism of action is not completely understood, but studies suggest it functions to produce withdrawal symptoms by competing for opiate receptor sites within the CNS (a competitive antagonist, not a direct agonist), thereby preventing the action of both endogenous and xenobiotic opiates on these receptors without directly producing any effects itself. When administered parenterally (e.g. intravenously or by injection), as is most common, naloxone has a rapid distribution throughout the body. The mean serum half-life has been shown to range from 30 to 81 minutes, shorter than the average half-life of some opiates, necessitating repeat dosing if opioid receptors must be stopped from triggering for an extended period. Naloxone is primarily metabolized by the liver. Its major metabolite is naloxone-3-glucuronide, which is excreted in the urine. Naloxone is useful both in acute opioid overdose and in reducing respiratory or mental depression due to opioids. Whether it is useful in those in cardiac arrest due to an opioid overdose is unclear. Naloxone is poorly absorbed when taken by mouth, so it is commonly combined with a number of oral opioid preparations, including buprenorphine and pentazocine, so that when taken orally, just the opioid has an effect, but if misused by injecting, the naloxone blocks the effect of the opioid. In a meta-analysis of people with shock, including septic, cardiogenic, hemorrhagic, or spinal shock, those who received naloxone had improved blood flow. Naloxone is also experimentally used in the treatment for congenital insensitivity to pain with anhidrosis, an extremely rare disorder (one in 125 million) that renders one unable to feel pain or differentiate temperatures. Naloxone can also be used as an antidote in overdose of clonidine, a medication that lowers blood pressure.

Mitragynine is the main active alkaloid constituent of the plant Mitragyna speciosa Korth. Mitragyna speciosa Korth. (M. speciosa), from the Rubiaceae family, is a tropical medicinal plant native to Southeast Asia. In Malaysia, M. speciosa leaves are known as Ketum or Biak, and in Thailand as Kratom. M. speciosa has been historically used in Southeast Asia as a stimulant drug and in its traditional context as a remedy for various symptoms. Pharmacological activities are mainly mediated via opioid receptors as well as neuronal Ca2+ channels, expression of cAMP and CREB protein and via descending monoaminergic system. Mitragynine acted as a partial agonist at mu-opioid receptors, in contrast, at kappa-opioid receptors, mitragynine was a competitive antagonist, similarly, mitragynine acted as an antagonist at delta-mu-opioid receptors, but with very low potency. Experimental studies in animals have now shown that mitragynine has an addictive potential, however, only at higher doses. Human users in countries of frequent use with a traditional context report a rather low daily consumption with only mild side effects. Kratom and mitragynine can be instrumentalized to enhance physical work power and endurance. A major reason for Kratom consumption is its reported efficacy to replace opiates in chronic users. This makes the Kratom plant preparation and also the isolated compound mitragynine interesting options to treat opiate addiction. In August 2016, the US Drug Enforcement Administration announced plans to classify kratom and its mitragynine constituents as Schedule 1 controlled substances.

LY2033298 is a selective allosteric modulator for muscarinic acetylcholine M4 receptor. It exerts antipsychotic action in animal models. The compound is able to modulate circadian activity rhythms and morphine-induced conditioned place preference in rats.

1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H-7) is an inhibitor of cAMP-dependent, cGMP-dependent, and Ca2+-phospholipid-dependent (protein kinase C) protein kinases at roughly equal concentrations. It is widely used to study protein kinase signaling both in vitro and in vivo.

Levomethadyl acetate (LAAM) is a synthetic opioid agonist with actions qualitatively similar to morphine (a prototypic mu agonist) and affecting the central nervous system (CNS) and smooth muscle. Principal actions include analgesia and sedation. Tolerance to these effects develops with repeated use. An abstinence syndrome generally occurs upon cessation of chronic administration similar to that observed with other opiates, but with slower onset, more prolonged course, and less severe symptoms. LAAM exerts its clinical effects in the treatment of opiate abuse through two mechanisms. First, LAAM cross-substitutes for opiates of the morphinetype, suppressing symptoms of withdrawal in opiate-dependent individuals. Second, chronic oral administration of LAAM can produce sufficient tolerance to block the subjective “high” of usual doses of parenterally administered opiates. Since the introduction of levomethadyl in 1995, the manufacturer has received increasing reports of severe cardiac-related adverse events, including QT interval prolongation, Torsades de Pointes and cardiac arrest. Other cardiac-related adverse events have also been reported, including arrhythmias, syncope, and angina. These events led to the removal of levomethadyl from the European market in March 2001. A very small number of patients may benefit from levomethadyl, but the risk of continued distribution and use no longer outweighs the overall benefits.

Chloral hydrate was discovered in 1832, and was used as a sedative in late 19th century. Chloral hydrate has not been approved by the FDA or the EMA, and is on the list of unapproved drugs that are prescribed for postoperative pain control, sedation and to prevent alcohol withdrawal and reduce anxiety associated with withdrawal of opiates or barbiturates. Mechanism of action of chloral hydrate is not known. It is generally believed that the central depressant effects are due to the principal pharmacologically active metabolite trichloroethanol, which has a plasma half- life of 8 to 10 hours, and acts by potentiating GABA-activated Cl currents.

Mianserin is a tetracyclic antidepressant used for the treatment of depression. It was investigated as an adjuvant for reduction of negative and cognitive symptoms of schizophrenia, as an aid for opioid detoxification therapy (where it reduced symptoms but lead to higher drop-out rate), and for the treatment of post-traumatic stress disorder (where it was ineffective). Mianserin has a broad spectrum of activity with the most potent binding to 5-HT2A, 5-HT2C, H1, alpha2A and alpha2C receptor.

Naltrexone is marketed as its hydrochloride salt, naltrexone hydrochloride, under the trade names Revia and Depade. A once-monthly extended-release injectable formulation is marketed under the trade name Vivitrol. VIVITROL is indicated for the treatment of alcohol dependence in patients who are able to abstain from alcohol in an outpatient setting prior to initiation of treatment with VIVITROL. VIVITROL is indicated for the prevention of relapse to opioid dependence, following opioid detoxification. Naltrexone is a pure opiate antagonist and has little or no agonist activity. The mechanism of action of naltrexone in alcoholism is not understood; however, involvement of the endogenous opioid system is suggested by preclinical data. Naltrexone is thought to act as a competitive antagonist at mc, κ, and δ receptors in the CNS, with the highest affinity for the μ receptor. Naltrexone competitively binds to such receptors and may block the effects of endogenous opioids. This leads to the antagonization of most of the subjective and objective effects of opiates, including respiratory depression, miosis, euphoria, and drug craving. The major metabolite of naltrexone, 6-β-naltrexol, is also an opiate antagonist and may contribute to the antagonistic activity of the drug. Low dose naltrexone is an “off label” use of naltrexone. Normal naltrexone usage to break addictions is 50mg – 100mg. Usage of low dose naltrexone ranges in the area of 3 mg – 4.5 mg dosing and is prescribed in an oral pill form and is quite inexpensive. For people with multiple sclerosis, the dosage of LDN ranges from 1.5 to 4.5 ml per day.